Drug & supplement interaction

Melatonin + Acetaminophen, Diphenhydramine, Pseudoephedrine

Acetaminophen, Diphenhydramine, Pseudoephedrine brand names: Contac Night Allergy Relief, Children's Tylenol Allergy, Cold Control.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Acetaminophen, Diphenhydramine, Pseudoephedrine falls into 3 drug categories that Melatonin can interact with; the most serious is rated moderate. Theoretically, taking melatonin might increase the sedative effects of CNS depressants.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions3
EvidenceD
What do Severity, Likelihood & Evidence mean?
Know someone taking this? Share
Facebook Post Reddit Email
On this page
Interaction report

Melatonin and Acetaminophen, Diphenhydramine, Pseudoephedrine

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

Melatonin interacts with whole categories of medication. Acetaminophen, Diphenhydramine, Pseudoephedrine falls into 3 of those categories, so it can interact with Melatonin in 3 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CNS DEPRESSANTS

1 of 3

Why this applies to Acetaminophen, Diphenhydramine, Pseudoephedrine

Acetaminophen, Diphenhydramine, Pseudoephedrine falls under CNS DEPRESSANTS — the group Melatonin interacts with.

Theoretically, taking melatonin might increase the sedative effects of CNS depressants.
Melatonin has sedative effects. Theoretically, concomitant use of melatonin with alcohol, benzodiazepines, or other sedative drugs might cause additive sedation.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the thing to keep an eye on with this combo product: it contains diphenhydramine, the same antihistamine found in Benadryl, which already makes a lot of people drowsy. Melatonin sends your brain an "it's bedtime" signal of its own. Stack the two together and that sleepy, foggy, slow-reaction feeling can add up. You might notice extra grogginess, dizziness, or trouble concentrating, which matters most if you plan to drive or are caring for someone.

One twist: this medicine also has pseudoephedrine, a stimulant decongestant that can be a bit activating, so people react in different ways. This concern is theoretical, based on how these ingredients work rather than strong studies, so don't panic. Just check with your pharmacist or doctor before pairing them, especially for kids.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed
Moderate

SEIZURE THRESHOLD LOWERING DRUGS

2 of 3

Acetaminophen, Diphenhydramine, Pseudoephedrine also falls under SEIZURE THRESHOLD LOWERING DRUGS.

Theoretically, taking melatonin with drugs that lower the seizure threshold might increase the risk of seizure activity.
Some clinical evidence suggests that melatonin may increase the frequency of seizures in certain patients, particularly children with neurological disabilities.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the deal with this combo product. The piece that interacts with melatonin is the diphenhydramine (the antihistamine in it). On paper, both melatonin and diphenhydramine can slightly lower the seizure threshold, so taking them together might, in theory, make a seizure a little more likely. This matters most for people who already have a seizure disorder, and a small amount of evidence has flagged it especially in children with neurological conditions.

For most healthy adults using this occasionally for a cold or allergies, this is a theoretical concern, not something proven to happen often. Still, expect this product itself to make you drowsy, and melatonin adds to that sleepiness. If you or your child has epilepsy, please check with your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351:1254. PubMed
  2. Stewart LS. Endogenous melatonin and epileptogenesis: facts and hypothesis. Int J Neurosci 2001;107:77-85.. PubMed
Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

3 of 3

Acetaminophen, Diphenhydramine, Pseudoephedrine also falls under CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES.

Theoretically, melatonin might increase levels of drugs metabolized by CYP1A2. Also, other CYP1A2 substrates might decrease the metabolism of melatonin, increasing melatonin levels.
Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes. Theoretically, combined administration of melatonin with drugs metabolized by the CYP1A2 enzyme might reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP1A2 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Moderate Likelihood Probable Evidence D

Interaction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports..

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

This combo product pairs a pain reliever (acetaminophen) with an antihistamine (diphenhydramine) and a decongestant (pseudoephedrine). The concern here is mostly on paper. Melatonin and these ingredients can lean on the same liver pathway (CYP1A2), so in theory melatonin could slow their breakdown a bit and let levels run slightly higher. None of these are prodrugs, so we'd expect their normal effects to be nudged up, not switched off.

What that might feel like: extra grogginess or next-day drowsiness from the diphenhydramine and melatonin both making you sleepy. Since this is theoretical and only moderate, most people do fine, but check with your pharmacist before stacking them, especially if you drive early or care for kids.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Yeleswaram, K., Vachharajani, N., and Santone, K. Involvement of cytochrome P-450 isozymes in melatonin metabolism and clinical implications. J Pineal Res 1999;26(3):190-191. PubMed
  2. Faber, M. S., Jetter, A., and Fuhr, U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol. 2005;97(3):125-134. PubMed
  3. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Melatonin Also Interacts With Other Medications

Melatonin has 1,115 moderate, 345 minor known drug interactions in our database — the Acetaminophen, Diphenhydramine, Pseudoephedrine one above is among them. If you take anything else, check it against the full list below.

Moderate 1,115 Minor 345 No known interaction 1,370 (incl. Acetaminophen, Diphenhydramine, Pseudoephedrine)
Taking anything else?

Check Another of Your Medications Against Melatonin

Covers the 2,830 medications we’ve checked against Melatonin. Pick one to open its full report.

From our Q&A

Questions About Melatonin or Acetaminophen, Diphenhydramine, Pseudoephedrine

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Melatonin or Acetaminophen, Diphenhydramine, Pseudoephedrine, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Acetaminophen, Diphenhydramine, Pseudoephedrine

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Acetaminophen, Diphenhydramine, Pseudoephedrine page lists 292 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: 1,4-butanediol (major), Activated Charcoal (major), Asarabacca (major), Beer (major) and Ephedra (major).

By severity: 15 major · 234 moderate · 43 minor.

From our pharmacist’s overview on the Acetaminophen, Diphenhydramine, Pseudoephedrine page

“A drink with this medicine is the risk I would flag first. Beer and wine both carry major ratings, well documented in humans, because alcohol deepens the sedation that diphenhydramine already causes.”

Reviewed by 2 · Jul 18, 2026

Open the Acetaminophen, Diphenhydramine, Pseudoephedrine interaction page

One more smart check

Taking Melatonin as Part of a Dietary Supplement Product? Check It for Interactions

We hold 2,885 real supplement products containing Melatonin, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Melatonin. Your product may carry other ingredients that interact with Acetaminophen, Diphenhydramine, Pseudoephedrine too, on top of Melatonin — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Melatonin and Acetaminophen, Diphenhydramine, Pseudoephedrine Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Melatonin
Top 5%

#55 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Acetaminophen, Diphenhydramine, Pseudoephedrine
Top 25%

#537 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Melatonin

What is Melatonin?

Melatonin
  • Trouble falling asleep (insomnia)
  • Jet lag
  • Delayed sleep phase syndrome
  • Non-24-hour sleep-wake disorder
  • Shift-work sleep problems
  • Sleep problems in some children with conditions like autism or ADHD

Melatonin is a hormone your body makes naturally to help control your sleep-wake cycle, and the supplement form is widely used to help with sleep timing problems and jet lag. The evidence is strongest for certain circadian (body-clock) disorders and is more mixed for everyday insomnia. It is generally well tolerated for short-term use, but talk with your pharmacist or doctor before starting, especially for children or during pregnancy.

Read the full Melatonin monograph & all interactions
Keep checking

Other Drugs & Melatonin

Browse every other medication we’ve checked against Melatonin — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
1,115Moderate
345Minor
1,369No known interaction
1,115 Moderate 345 Minor 1,369 No interaction
Moderate

1,115 interactions

Showing 60 of 1,115 moderate interactions — see all 1,115 on the Melatonin page.

Minor

345 interactions

Showing 60 of 345 minor interactions — see all 345 on the Melatonin page.

No interaction 1,369 drugs checked — show the list

We also checked Melatonin against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,369 medications checked with no known interaction — see the full Melatonin list.

See the full Melatonin interactions page
See every supplement checked against Acetaminophen, Diphenhydramine, Pseudoephedrine, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Melatonin monograph › Uses, safety, and every drug interaction in one place Acetaminophen, Diphenhydramine, Pseudoephedrine supplement interactions › Every supplement checked against Acetaminophen, Diphenhydramine, Pseudoephedrine, ranked by severity Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Melatonin and Acetaminophen, Diphenhydramine, Pseudoephedrine Together: Common Questions

Can you take Melatonin with Acetaminophen, Diphenhydramine, Pseudoephedrine?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 3 interactions listed for Melatonin and Acetaminophen, Diphenhydramine, Pseudoephedrine?
Acetaminophen, Diphenhydramine, Pseudoephedrine belongs to more than one drug category, and Melatonin interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Melatonin and Acetaminophen, Diphenhydramine, Pseudoephedrine interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Acetaminophen, Diphenhydramine, Pseudoephedrine and Melatonin?

Our pharmacists answer your medication & supplement questions — free.

Ask a pharmacist

This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.